West worked at WBCN in Boston, performing daily on the air on The Big Mattress show, then moved to New York City in 1988, working at K-Rock Radio (92.3 FM WXRK). West became a regular on The Howard Stern Show at that time until leaving in 1995. West moved to Los Angeles, where he found success as a voice actor and performer.

West's first two high-profile roles, on Doug and The Ren & Stimpy Show, came almost simultaneously and were on two of the first original three Nicktoons (the other being Rugrats). Over his career, West has been the voice talent for close to 120 different characters including some of the most iconic animated figures in television history. He has become one of the few voice actors who can impersonate Mel Blanc in his prime, including characterizations of Bugs Bunny and Daffy Duck, the voice Arthur Q. Bryan used for Elmer Fudd, as well as other characters from Warner Bros. cartoons. In 1998, Entertainment Weekly described West as "the new Mel Blanc" and noted his ability to mimic well-known voices,[9] though he would rather develop original voices.[9] West's favorite characters are Philip J. Fry and Stimpy, both of which he originated.[10] West has been very outspoken over his displeasure about the influx of movie star actors providing voice-over for films and major shows.[11][12] West has stated that he did not like the Disney version of Doug and that he "couldn't watch" the show.[13][14] West was the voice of the show's namesake, Geeker, throughout Project Geeker's 13-episode run. West was the voice of Zim in the original pilot for Nickelodeon'sInvader Zim.[citation needed]Richard Horvitz was chosen for the series role because West's voice was too recognizable, according to Invader Zim creator Jhonen Vasquez during DVD commentary. West is the voice of "Red" in numerous M&M commercials as well as the 3-D movie "I Lost my M in Vegas", currently playing at M&M's World in Las Vegas, NV. West also voices a number of characters in the series Rick & Steve: The Happiest Gay Couple in All the World. He does not play a regular character in that series but appears in almost every episode of the show voicing various minor and one-off characters. West voiced the character Moobeard in Moobeard the Cow Pirate, a short animation featured on Random! Cartoons, and reprises his role as Elmer Fudd in Cartoon Network's series The Looney Tunes Show. West provides the voice for the elephant/van Ellyvan in the Playhouse Disney show Jungle Junction. In 1999, he also had a cameo in the Emmy Award-winning cartoon Dilbert.

West provided the voice of Stimpy in Nickelodeon's The Ren & Stimpy Show from 1991 until 1996, and he later provided the voice of Ren Höek from 1993 to 1996 when Ren's original voice and series creator John Kricfalusi was fired by Nickelodeon for delivering un-airable episodes. West performed other characters on the series as well, such as Mr. Horse (another role that West was issued after Kricfalusi's departure) and the "Announcer/Salesman" of such shorts as the "Log" ads (a voice West would use years later as the Narrator for The Weird Al Show).

According to West, he was originally supposed to do the voice of both Ren and Stimpy (and performed both characters on the tape that was used to sell the show to Nickelodeon), but then Kricfalusi decided to do the voice of Ren himself once the show was sold and he had West on board as part of the selling point.[15] However, West provided Ren's maniacal laughter when John Kricfalusi was the voice of Ren.

West's roles in Futurama include Philip J. Fry, Professor Farnsworth, Zapp Brannigan, Dr. Zoidberg and various other incidental characters. As he and other Futurama cast and crew point out in DVD commentaries, West voiced so many characters throughout the series that conversations are often held entirely between characters he is voicing.

West went into the Futurama auditions and was asked to try out for, as he says, "just about every part";[16] eventually landing the Professor, Zoidberg, and Zapp Brannigan. West later got the role of Fry, which originally had gone to Charlie Schlatter.[17] While West is known for doing many different and unique voices, the voice he does for Philip J. Fry is often considered to be closer to his natural voice than any other character he has done (in an audio commentary, he states Fry is just himself at age 25).[18] This similarity, West acknowledges, was done purposefully in order to make it harder to replace him in the part[19] along with placing more of himself personally into the role (DVD commentary).

The role of Zapp Brannigan was created for Phil Hartman, but he died before the show started and West was given the role. West has described his interpretation of Zapp Brannigan's voice as an imitation of Hartman, but described the actual vocalizations of the character as being based on "a couple of big dumb announcers I knew."[20]

Futurama was renewed by Comedy Central as four direct-to-DVD films broken into 16 television episodes.[21] West reprised his roles for these films and was signed on for two new 26-episode production seasons (four 13-episode air seasons) of Futurama which aired summers of 2010–2013.[22]

West was the announcer of the program Screen Gems Network which ran from 1999–2001. He was the promotional announcer for The Comedy Channel before it merged with HA! to become Comedy Central. Over his career, Billy West has voiced multiple characters in television commercials.
These include (but are not limited to):

West appeared on Ken Reid's TV Guidance Counselor Podcast on January 30, 2015. The episode was recorded live at The Smell in Downtown Los Angeles during the third annual Riot LA Comedy Festival.

West began his own podcast show in July 2015. It features him doing numerous characters per episode, recurring segments such as "Song Demolition" and "Billy Bastard – Amateur Human Being", and special guest Jim Gomez.[25]

West is a guitarist and singer-songwriter with a band called Billy West and The Grief Counselors. They have released their first album, Me-Pod.[26] West has toured as a guitarist for Roy Orbison and Brian Wilson.[9]

In 1982, West sang lead, doing an impersonation of Mike Love, on a Beach Boys-inspired tune, "Another Cape Cod Summer This Year," by studio band ROUTE 28, written and produced by Erik Lindgren on his Arf! Arf! Records label.[citation needed]